We will evaluate the overall hypothesis that the combined treatment with the vaccines that induce particular chemokine receptors (CKR) on tumor-specific effector T cells with the treatments that induce the production of the relevant chemokines selectively within tumors, will result in therapeutic synergism, by directing tumorspecific T cells to tumors. Our proposal is based on our development of a new dendritic cell variant (aDC1s) with a unique ability of to induce a defined pattern of CKRs on tumor-specific T cells (selectively-enhanced expression of CXCR3 and CCR5), and our development of several complementary strategies to selectively enhance the production of the relevant chemokines in different tumor tissues. This Program involves three Research Projects: Project 1: Tumor-Specific Chemokine Modulation in Colorectal Cancer versus Melanoma;Project 2: Type-1 Antigen Presenting Cells in the CMS Tumors: the Key to Efficient Anti-tumor Immunity;Project 3: Tumor-selective Oncolytic Vaccinia Virus and aDC1-based Vaccine as a Combination Therapy for Colorectal Cancer. Our ongoing clinical trials in melanoma, colorectal cancer, and glioma, will provide the patient material for the laboratory studies proposed in years 1-3. The paradigms and methods developed within this period will result in the clinical introduction of new combination therapies of cancer (vaccination + chemokine-targeting regimen) that will be clinically tested in years 4-5 of this Program.